It is estimated that 4 million children die of severe lower respiratory tract disease per year in developing countries. Viruses probably cause the majority of lower respiratory tract disease, however, bacteria appear to be responsible for most of the severe mortality and morbidity. Although it has been difficult to establish the etiologic agents responsible for lower respiratory tract disease, the most common bacterial agents observed are Haemophilus influenzae and Streptococcus pneumoniae. Several studies have now documented that a substantial fraction of the H. influenzae isolates are nontypable. Granoff, Weinberg and co-workers have characterized Haemophilus isolates from the blood of patients with lower respiratory tract disease in Pakistan. Thirty-two percent of the 105 Haemophilus isolates they examined were nontypable. Isolates from patients with invasive disease in Papua New Guinea and the Philippines have also been examined by these workers. Fifteen percent of the isolates from the Papua New Guinea collection and 37% of the isolates from the Philippine collection were nontypable. Thus, the available data indicate that nontypable Haemophilus is an important cause of lower respiratory tract disease in children in the developing world. In the developed world, NTHI are an important cause of infections of mucosal surfaces such as otitis media, sinusitis and bronchitis. It is not clear at present whether or not the NTHI isolates from children in the developing world are different from the NTHI isolates in the developed world which are responsible for 1) mucosal surface infections in children, 2) pneumonia and other serious infections in immunocompromised patients, or 3) exacerbations of chronic bronchitis in adults. The overall goals of the proposed studies are 1) to characterize the nontypable influenzas strains which are responsible for severe lower respiratory tract disease in children in the developing world and 2) to develop strategies for creating new vaccines for children at risk for contracting severe lower respiratory disease caused by these organisms. These studies will also provide a foundation for developing vaccines for prevention of otitis media, sinusitis, and bronchitis caused by nontypable H. influenzae.